scholarly journals A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Alex Sternberg ◽  
Rebecca H. Boucher ◽  
Helen C Coulthard ◽  
Manoj Raghavan ◽  
Dominic J. Culligan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Immune Thrombocytopenic Purpura ◽  
Research Funding ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
Thrombopoietin Receptor ◽  
Phase 1B ◽  
Grade 3

Background: Azacitidine (AZA) based therapy is a standard of care in IPSS INT-2/High MDS/low blast count AML and CMML-2. Thrombocytopenia is an adverse prognostic factor in MDS; increased severity correlates with haemorrhagic complications and shorter AML progression time, and early platelet recovery after AZA is linked to better outcomes. Accumulation of AZA doses is important to patient response, but initial treatment with AZA can aggravate thrombocytopenia and impact outcome. Eltrombopag (ELT) is a thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura. ELT has shown efficacy in low risk MDS and reduces thrombocytopenic events in advanced MDS and AML. The ELASTIC trial (ISRCTN05858391) is a single-arm phase 1b dose-finding study examining the safety and tolerability of ELT/AZA in patients with MDS/AML with expansion cohort (n=10) at MTD. We investigated if ELT/AZA would lead to earlier platelet recovery and improve AZA efficacy. Although a Phase 3 study testing ELT/AZA (SUPPORT) was terminated due to futility during the ELASTIC trial, we reasoned that drug sequencing may affect outcome. As ELASTIC patients received an ELT pre-phase, ELASTIC was run to completion. Methods: Patients with IPSS INT-2 or High MDS/CMML-2/AML <30% blasts were treated in a 3+3 trial design in cohorts of ≥3 patients with 25, 50, 100, 200 or 300mg/day ELT. AZA (75mg/m2) was administered for 7 days of a 28 day cycle. All patients received ELT and AZA and were treated for maximum 6 cycles. ELT was administered from day -7 of cycle 1. ELT continued through cycles 1-2 and 4-6 with no ELT during cycle 3. Patients were evaluated after cycle 1 for dose-limiting toxicities (DLTs). The primary outcome was safety and tolerability (including establishing the MTD) of ELT in combination with AZA. Key secondary outcomes were the effect of ELT on platelet counts, platelet transfusions and marrow blast percentage. Full blood count was measured weekly over the first 13 weeks and monthly thereafter; bone marrow was taken on day 8 of ELT and at the end of cycles 3 and 6. Results: Thirty-one patients were recruited from November 2014 to August 2018. Thirty (median age 74, range: 62-86) were evaluable for analysis in the safety population (AML=5, IPSS INT-2 MDS=12, IPSS High MDS=12, CMML-2=1); 1 patient was ineligible post registration. 11/30 (37%) were IPSS good risk, 3/30 (10%) intermediate risk and 14/30 (47%) high risk (2 unknown). ELT was well tolerated up to 300mg (25mg=5, 50mg=3, 100mg=4, 200mg=4, 300mg=14) and was safely combined with AZA. There were no DLTs in the DLT evaluable patients (n=15). The MTD was established as 300mg (n=14). There were 3 SUSARs, 19 SAEs, 28 SARs and 87 episodes of grade 3/4 AEs. There were 16 episodes of grade 3/4 neutropenia and 11 episodes of grade 3/4 anaemia. Five patients discontinued treatment due to toxicity (25mg=2, 300mg=3), 6 due to death (pneumonia=2, disease-related=4, ischaemic heart disease=1) and 1 withdrew. Platelet responses were seen at ELT 50mg and higher. At the MTD, median platelet count at baseline was 37 (IQR: 25-52), rising to 77 (IQR 50-108.5) and 74 (IQR: 32-430) at cycle 2 and 3 respectively. The median platelet nadir was 20.5 (IQR: 11-25) and 42 (IQR 18.5-51.5) after cycle 1 and 2 dropping to 20 (IQR: 9-160) after cycle 3 when ELT was stopped. Mean platelet transfusions did not change with ELT dose. There was no increase in delays to AZA dosing across the ELT dose cohorts. There was no change in bleeding incidents when patients received ELT. Overall, there was no increase in bone marrow blast percentage from baseline. The cycle 3 marrow aspirate was reached by 27/30 (90%) and 11/30 (37%) reached the cycle 6 marrow aspirate. At the end of 3 cycles there were 21 non-responders and 10 responders (CR=3, marrow CR=4, PR=3, SD=9). At the end of 6 cycles there were 22 non-responders and 9 responders (CR=3, marrow CR=4, PR=2, SD=5). 6/14 (43%) treated at the MTD responded while 3/16 (19%) treated at below the MTD responded. Conclusions: The combination of ELT with AZA is safe and tolerable. Clinically meaningful responses in platelets were seen in patients receiving 50mg or more ELT. At the MTD, there was a noticeable drop in platelet nadir in cycle 3 when patients were not receiving ELT. No change in platelet transfusion was identified across cohorts. The results suggest that an ELT pre-phase may improve platelet responsiveness in patients treated with AZA and warrants further exploration. Disclosures Sternberg: Celgene/BMS: Honoraria, Research Funding; GSK/Novartis: Honoraria, Research Funding. Raghavan:Celgene UK: Speakers Bureau. Culligan:Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Diiachi-Sankyo: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria. Cargo:Novartis: Honoraria. Vyas:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Astellas: Speakers Bureau; AbbVie: Speakers Bureau. OffLabel Disclosure: Eltrombopag is a second generation thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura.

Helicobacter pylori infection and chronic immune thrombocytopenic purpura: long-term results of bacterium eradication and association with bacterium virulence profiles

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3833-3841 ◽  
Author(s):  
Giovanni Emilia ◽  
Mario Luppi ◽  
Patrizia Zucchini ◽  
Monica Morselli ◽  
Leonardo Potenza ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Chronic Gastritis ◽  
Immune Thrombocytopenic Purpura ◽  
Long Term Results ◽  
Platelet Response ◽  
Related Factors ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
H Pylori

AbstractEradication of Helicobacter pylori may lead to improvement of chronic immune thrombocytopenic purpura (ITP), although its efficacy over time is uncertain. We report the results of H pylori screening and eradication in 75 consecutive adult patients with ITP. We also used molecular methods to investigate lymphocyte clonality and H pylori genotypes in the gastric biopsies from 10 H pylori–positive patients with ITP and 19 H pylori–positive patients without ITP with chronic gastritis. Active H pylori infection was documented in 38 (51%) patients and successfully eradicated in 34 (89%) patients. After a median follow-up of 60 months, a persistent platelet response in 23 (68%) of patients with eradicated infection was observed; 1 relapse occurred. No differences in mucosal B- or T-cell clonalities were observed between patients with ITP and control participants. Of note, the frequency of the H pylori cagA gene (P = .02) and the frequency of concomitant H pylori cagA, vacAs1, and iceA genes (triple-positive strains; P = .015) resulted statistically higher in patients with ITP than in control participants. All asymptomatic H pylori–positive patients with ITP were suffering from chronic gastritis. Our data suggest a sustained platelet recovery in a proportion of patients with ITP by H pylori eradication alone. Overrepresentation of specific H pylori genotypes in ITP suggests a possible role for bacterium-related factors in the disease pathogenesis.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2553-2553
Author(s):  
Daniel J. DeAngelo ◽  
Alison R. Walker ◽  
Richard F. Schlenk ◽  
Jorge Sierra ◽  
Bruno C. Medeiros ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Phase 1B ◽  
Grade 3 ◽  
Advisory Role

Abstract Background: For patients (pts) with acute myeloid leukemia (AML) with poor prognostic indicators, such as unfavorable cytogenetics or secondary AML, overall and event-free survival (EFS) rates are much worse, highlighting the critical need for more effective therapeutic modalities. Increasing evidence implicates epigenetic processes in the development of AML. Panobinostat (PAN), a potent pan-deacetylase inhibitor, has been shown to augment the effects of standard chemotherapies (anthracyclines and Ara-C) in preclinical studies with AML cells. These preclinical results led to a phase 1b study of PAN in combination with idarubicin and Ara-C in pts with high-risk AML. Methods: The trial included younger pts (≥ 18 y and ≤ 65 y) with newly diagnosed high-risk AML, defined as: treatment-related AML, AML following previously diagnosed myelodysplasia or medical history of relevant hematologic disorders, and presence of unfavorable cytogenetics. The primary objective was determination of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of PAN when given in combination with idarubicin and Ara-C. Secondary objectives included safety, efficacy, and pharmacokinetics (PK). Exploratory endpoints included assessment of the relationship between efficacy and PK parameters and 1-year EFS. The study examined escalating doses (15-25 mg) of PAN given 3 times per wk for 2 wk starting on day 8 of a 28-day cycle (ie, D8, D10, D12, D15, D17, D19) in combination with standard induction doses of idarubicin (12 mg/m2/d; D1-D3) and Ara-C (100 mg/m2/d; C1, D1-D7). After 2 cycles, pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) moved to a consolidation phase with a combination of high-dose Ara-C and PAN at the dose received during induction. After determination of the RP2D, additional pts were enrolled in the expansion phase and treated at the RP2D dose. Results: A total of 46 pts with a median age of 55.5 y (range, 19-65 y) were enrolled in the study (34 in the dose-escalation phase [15 mg, n = 11; 20 mg, n = 15; 25 mg, n = 8] and 12 in the dose-expansion phase). Seven dose-limiting toxicities were observed in the escalation phase: 4 of 12 pts in the 20-mg group (left ventricular systolic dysfunction [n = 2], hepatosplenic candidiasis [n = 1], increased QTCF [n = 1]) and 3 of 7 pts in the 25-mg group (febrile neutropenia [n = 2], grade 3 diarrhea [n = 1]). Based upon the Bayesian linear regression model, the upper limit (≤ 25% probability of excessive toxicity in > 33% of pts) was not reached for determination of MTD. The RP2D of PAN was 20 mg. Among the 27 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic, including febrile neutropenia (59.3%), thrombocytopenia (48.1%), and anemia (40.7%). Although most pts experienced gastrointestinal AEs, they were largely grade ≤ 2 (all grades, 74.1%; grade 3/4, 11.1%). AEs led to discontinuation in 15% of pts treated at the RP2D. Four pts (3 of 46 during induction and 1 of 19 during consolidation) treated with RP2D died during treatment. Of the on-treatment deaths, 1 (grade 4 sepsis) was potentially related to study drug, whereas the remaining 3 (progressive AML, ischemic stroke, and cerebral hemorrhage) were determined to be unrelated. The geometric mean AUC0-24 of PAN after oral dosing increased with increasing PAN dose (42.5 hr•ng/mL [15 mg], 62.6 hr•ng/mL [20 mg], and 74.6 hr•ng/mL [25 mg]). However, AUC0-24 was higher in the expansion phase (92.7 hr•ng/mL) than at 25 mg in the escalation phase, with high variability (coefficient of variation, 32.3% [expansion]; 45.5% [25-mg escalation]). Among pts treated at the RP2D, 44.4% and 11.1% achieved CR and CRi, respectively (CR/CRi, 56%). In the subset of pts in the RP2D, no relationship was found between AUC0-24 and response rates. In the overall population, the 1-year EFS rate was 78.3%. Conclusions: The data from this study showed high variability in PAN PK and largely overlapping exposure between dose levels. Overall, these data demonstrate a safety profile consistent with those of single-agent PAN and the combination of Ara-C and idarubicin. Disclosures DeAngelo: Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sierra:Novartis: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Ocio:Novartis: Consultancy, Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Valera:Novartis: Employment. Wegener:Novartis: Employment. De:Novartis: Employment. Mu:Novartis: Employment. Binlich:Novartis: Employment. Stuart:Novartis: Research Funding.

scholarly journals Bone marrow reticulin and collagen content in patients with adult chronic immune thrombocytopenic purpura: A Danish nationwide study

2010 ◽  
Vol 85 (12) ◽  
pp. 930-934 ◽  
Author(s):  
Marianne Schmidt Ettrup ◽  
Annette Østergaard Jensen ◽  
Malene Cramer Engebjerg ◽  
Dóra Körmendiné Farkas ◽  
Mette Nørgaard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Thrombocytopenic Purpura ◽  
Collagen Content ◽  
Thrombocytopenic Purpura ◽  
Nationwide Study ◽  
Chronic Immune Thrombocytopenic Purpura

Time to Splenectomy Failure in Patients with Recurrent or Refractory Chronic Immune Thrombocytopenic Purpura.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3522-3522
Author(s):  
Gregory Cheng ◽  
Terry Gernsheimer ◽  
Harold J. Olney ◽  
James B. Bussel ◽  
Palvi Shah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Thrombocytopenic Purpura ◽  
Research Funding ◽  
Therapeutic Option ◽  
Advisory Committees ◽  
Thrombocytopenic Purpura ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 3522 Poster Board III-459 INTRODUCTION Splenectomy has been perceived as a potentially curative treatment for patients with chronic immune thrombocytopenic purpura (ITP). Historical data demonstrate that the risk of relapse is between 33% and 50% in patients with long-term follow-up (Fabris, Br J Haematol, 2001; Schwartz, Am J Hematol, 2003). No clear pattern of time to relapse after splenectomy has been described which complicates the decision making process for physicians who are considering this irreversible therapeutic option. Splenectomized patients are at risk for: early and late surgical complications (Kojouri, Blood, 2004; Portielje, Blood, 2001); infections secondary to impaired immunity (BCSH 1996; Moffett, JAAPA, 2009; Oren 2008); thrombotic and/or cardiovascular disease (Schilling, J Thromb Haemost, 2008; Fontana, Thromb Res, 2008); and pulmonary hypertension (Schilling, J Thromb Haemost, 2008; Bonderman, Circulation, 2007). Splenectomy requires preoperative vaccinations, general anesthesia with antibiotic prophylaxis, and subsequent long-term vigilance with early antibiotic treatments. These factors not only impact the utilization of medical resources but also, due to clinically problematic outcomes, may lead to a requirement for additional treatments. OBJECTIVE: To describe the time from splenectomy to splenectomy failure among patients with chronic ITP enrolled in the eltrombopag clinical program. METHODS: Date of splenectomy and prior medications for ITP were reviewed in patients enrolled in 5 clinical trials using eltrombopag. Splenectomy was considered to have failed upon administration of the first treatment for ITP after surgery or when patients were not able to taper or interrupt concomitant ITP treatments in the 30 days following splenectomy. Of the 495 patients enrolled in the ITP program, 192 (39%) were splenectomized and 185 patients were evaluable for this analysis. The analysis does not describe overall effectiveness of splenectomy as the patient population is limited to splenectomy failure patients who required additional treatment for their ITP. RESULTS: Fifty-one percent of patients required ITP medications within 1 year of splenectomy (Figure 1). Five years after splenectomy, 27% of patients still had a response; this percentage decreased to 18% after 10 years. CONCLUSION: This retrospective analysis demonstrates that success of splenectomy appears to diminish over time. In patients requiring further ITP treatment, most splenectomized patients who relapse do so within 5 years. The treatment of chronic ITP has advanced as more data on the safety and efficacy of new medications like the thrombopoietin receptor agonists have become available. As physicians and patients become more familiar with the risks and benefits of all treatments, options other than splenectomy may be preferred for certain patients. Disclosures: Cheng: GlaxoSmithKline: Research Funding. Gernsheimer:GlaxoSmithKline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Olney:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Shah:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment. Grotzinger:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment.

A Phase 1b/2a Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve, Refractory to or Have Relapsed on 5-Azacitadine: a Preliminary Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3263-3263 ◽  
Author(s):  
Gautam Borthakur ◽  
James M. Foran ◽  
Eunice S. Wang ◽  
Amol Rakkar ◽  
Steven Hager ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Clinical Activity ◽  
Phase 2 ◽  
First Line ◽  
Smac Mimetic ◽  
Blast Count ◽  
Phase 1B ◽  
Grade 3 ◽  
Line Setting

Abstract 5-azacitidine (5-AZA) is standard of care in the first-line setting for higher-risk patients with Myelodysplastic Syndrome (MDS). However, 40-50% of patients are refractory to 5-AZA and most responders ultimately demonstrate disease progression within 2 years, often progressing to AML. For patients refractory to 5-AZA, 2-year survival probability is low (15%). Thus, there is a need for more effective initial and second-line therapies for patients with higher-risk MDS. The Inhibitors of Apoptosis (IAP) Proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in MDS, suggesting a potential path for therapeutic intervention. SMAC (second mitochondrial activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-kB and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic with improved tolerability and therapeutic index compared to other SMAC mimetics. This Phase Ib/2a study was designed primarily to determine the MTD and recommended Phase 2 dose and schedule of birinapant in combination with 5-AZA in patients with higher-risk MDS who are naïve or have relapsed or are refractory to 5-AZA. To date, 11 patients have been enrolled in the Phase 1b portion of the study, including 7 with IPSS classification high-risk MDS (5 male, 2 female; median age 75, range 64-82) and 4 with intermediate-risk MDS (2 male, 2 female; median age 72.5, range 65-84). All patients received standard 5-AZA, administered via either intravenous (IV) or subcutaneous (SC) routes, at 75 mg/m2 for 7 days of a 28-day cycle in combination with birinapant. Birinapant was administered IV twice weekly (Days 1 and 4) for either 3 of 4 weeks or 4 of 4 weeks per 28-day cycle at a dose of 13 mg/m2. No cycle 1 dose-limiting toxicities have been observed. Adverse events ≥ Grade 2 observed in two or more patients and judged to be related to treatment were rash/pruritis (Grade 2, 2 patients), thrombocytopenia (Grade 4, 2 patients) and neutropenia (Grade 4, 1 patient; Grade 3, 1 patient). Two SAEs, Grade 3 abdominal soft tissue necrosis with abdominal pain in the area of subcutaneous injections of 5-AZA, and Grade 3 cellulitis were judged to be related to treatment. These local injection site reactions/cellulitis were more severe than usually expected with SC 5-AZA, suggesting an on target pharmacodynamic (TNF mediated) localized synergistic effect in skin, but were not observed with IV administration. Both occurred after cycle 1 and were not considered DLTs. Data showing inhibition of NF-kB, a downstream pro-survival molecule activated by IAPs, in circulating blast cells from patients treated with birinapant at a dose of 13 mg/m2 twice weekly for 3 weeks out of 4, suggests that birinapant is pharmacologically active at this dosing schedule. Based on these and other pharmacodynamic data, despite not determining the formal MTD, the Phase 2 dosing regimen has been established as birinapant administered at 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle in combination with 5-AZA at 75 mg/m2 by IV infusion for 7 days of a 28-day cycle. Although not a primary endpoint, evidence of clinical activity in 5-AZA resistant/refractory patients was observed in 2 of 11 patients to date, with an additional good clinical response in a 5-AZA naive high-risk MDS/CMML patient. One patient with prior 5-AZA-refractory MDS (cytogenetics: hypodiploid and +11q) showed bone marrow (BM) blast count reduction from 25% to 2% after 1 cycle of 5-AZA/birinapant treatment. Another patient with MDS (cytogenetics: +X; +19; +21) refractory to single-agent 5-AZA showed BM blast count reduction from 21% to 7% after 2 cycles. A third patient with treatment-naïve MDS/CMML-2 (cytogenetics: 46, XY, inv(6)(p11.2q15), t(6;21)(q21;q22) ) who had received prior hydroxyurea demonstrated BM blast count reduction from 17% to 2% after 3 cycles and underwent hematopoietic stem cell transplant. Several patients remain on study and are in active follow-up. This Phase 1b trial provide data for an acceptable safety profile of the first combination of a SMAC mimetic (birinapant) administered with IV 5-AZA. Early signs of clinical activity including in 5-AZA naïve and refractory patients were observed. These results provide rationale for a randomized Phase 2 study comparing birinapant in combination with 5-AZA against 5-AZA alone in the first-line setting for patients with higher-risk MDS. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Foran:TetraLogic Pharmaceuticals: Research Funding. Wang:Tetralogic Pharmaceuticals: Research Funding. Rakkar:Tetralogic Pharmaceuticals: Research Funding. Hager:Tetralogic Pharmaceuticals: Research Funding. Frey:Tetralogic Pharmaceuticals: Research Funding. Andreeff:TetraLogic Pharmaceuticals: Research Funding. Carter:Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Russell:Tetralogic Pharmaceuticals: Employment. Tibes:Tetralogic Pharmaceuticals: Research Funding.

scholarly journals Role of Helicobacter pylori Eradication Therapy on Platelet Recovery in Chronic Immune Thrombocytopenic Purpura

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Khan Sheema ◽  
Ujjan Ikramdin ◽  
Naz Arshi ◽  
Naz Farah ◽  
Sheikh Imran
Keyword(s):  
Bone Marrow ◽  
Helicobacter Pylori ◽  
Immune Thrombocytopenic Purpura ◽  
Eradication Therapy ◽  
Bone Marrow Examination ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
Chronic Itp ◽  
H Pylori

Background. Idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder in which the immune system destroys native platelets. In this condition an autoantibody is generated against a platelet antigen. ITP affects women more often than men and is more common in children than adults. Objective. To assess the effect of Helicobacter pylori eradication therapy (HPET) on platelet count in Helicobacter pylori associated chronic immune thrombocytopenic purpura (chronic ITP) in adult. Materials and Methods. It is an interventional prospective study conducted at Liaquat University of Medical and Health Sciences, Jamshoro, from 2014 to 2015. A set of 85 patients diagnosed with chronic ITP were included in the study via convenient sampling. Patients with platelets count < 100 × 109/L for >3 months were selected. They were posed to first-line investigations which comprised complete blood count (CBC) and peripheral blood smear examination followed by second-line tests including bone marrow examination and Helicobacter pylori stool specific antigen (HpSA-EIA). Standard H. pylori eradication therapy was offered and the patients were assessed at regular intervals for 6 months. Results. Of the 85 study patients, 32 (37.6%) were male and 53 (62.3%) were female. Mean ages of H. pylori positive and negative subjects were 43.89 ± 7.06 and 44.75 ± 7.91 years, respectively. Bone marrow examination confirmed the diagnosis and excluded other related BM disorders. H. pylori stool antigen (HpSA) was detected in 34 (40%) patients and hence regarded as H. pylori positive; the rest were negative. Treatment with eradication therapy significantly improved the mean platelet counts from 48.56±21.7 × 109/l to 94.2±26.8 × 109/l. Conclusion. We concluded that the anti-H. pylori eradication therapy improves blood platelet counts in chronic immune thrombocytopenia.

scholarly journals Maintenance Treatment with Guadecitabine (SGI-110) in High Risk MDS and AML Patients after Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Betul Oran ◽  
Gheath Alatrash ◽  
Amin M. Alousi ◽  
Rohtesh S. Mehta ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Study Drug ◽  
Bone Marrow Suppression ◽  
Efficacy And Safety ◽  
Disease Relapse ◽  
Interim Analyses ◽  
Grade 3 ◽  
Count Recovery

Background: Disease relapse remains to be the one of the major reasons of treatment failures after allogeneic stem cell transplantation (allo-SCT) in AML and MDS patients (pts). SGI-110 is a next generation hypomethylating agent that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. We present interim results of a single arm phase II trial evaluating the efficacy and safety of SGI-110 in AML/MDS pts. to improve transplant outcomes. Methods: In this study, there are 3 treatment cohorts defined by disease status after transplant with different primary outcomes of interest. Cohort 1 includes AML/MDS pts. with morphological relapse after transplant; cohort 2 pts with minimal residual (MRD) and cohort 3 pts with no evidence of disease. As of June 2020, 54 pts have enrolled. Herein, we report the interim analyses of 22 pts treated in cohort 3 and received SGI-110 as post-transplant maintenance while in remission. Other cohorts' results will be reported separately. The maintenance cohort includes high risk AML/MDS pts aged 18-75. High risk MDS is defined as having (1) poor or very poor cytogenetics by revised-IPSS or (2) monosomal karyotype or (3) bone marrow blast count &gt; 5% before transplant; high risk AML as (1) adverse risk group by European LeukemiaNet (ELN) or (2) presence of MRD or active disease at transplant. Therapy-related AML/MDS is included. Pts. are excluded in the presence of (1) active acute graft versus host disease (GvHD), (2) uncontrolled systemic infection, or (3) concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus. The study intervention includes SGI-110 given as 30 mg/m2/day subcutaneously for 5 consecutive days every 28 days until completion of 12 cycles, disease relapse, or experience of unacceptable toxicity. SGI-110 is initiated between 42 to 100 days following allo-SCT if there is adequate engraftment with absolute neutrophil count &gt;/= 1.0 x 109 /L; platelet &gt;/= 50 x 109 /L and no documented evidence of relapse. Treatment delays up to 70 days and dose reductions are allowed per protocol. The primary endpoint for this cohort is relapse-free survival (RFS) time defined as either time to disease progression or death whichever happened first. The maximum planned sample size is 40. Results: As of June 2020, 22 pts were enrolled; M/F, 12/10, median age, 62 (range 18 to74). Of 11 AML pts., ELN risk category was adverse in 8, intermediate in 2 and favorable in 1. Of 11 MDS pts, 6 had poor/very poor and 4 good and 1 intermediate risk cytogenetic abnormalities by revised-IPSS. Of 22, 6 were in complete remission with count recovery at transplant. Median time to initiation of first cycle of maintenance with SGI-110 was 59.5 days (range, 43 to 114 days). So far, 14 pts of 22 were taken off the study; 6 due to disease relapse, 4 completed planned 12 cycles of treatment, 1 lost insurance, 1 withdrew the consent, 1 had travel issues due to COVID19 pandemic and 1 had pulmonary complications unrelated to study drug. Currently, 8 remain to be on the study. Median number of treatment cycles administered have been 4 (range, 1 to 12). Of 22, 7 pts. required the SGI-110 dose to be reduced down to 20 mg/m2/dayX5 days and 1 patient to 20 mg/m2/dayX3 days to be able to continue the treatment. At a median follow-up of 13.1 months for survivors (n=17), RFS and overall survival at 1-year was 66.3% (95% confidence interval (CI)=42% to 82.3%) and 88.9% (95%CI=61.8 to 92.2%) respectively (Figure) During the study, 353 AEs observed with 125 cycles of SGI-110 treatments. Of 353, 287 (81.3%) were attributable to SGI-110 and 133 of 287 (46.3%) were grade 3 or higher in severity. Most of the grade 3 or higher AEs were related with bone marrow suppression; 71 (25%) thrombocytopenia, 64 (22%) neutropenia, 67 (23%) leukopenia and 8 (2%) anemia. Of 22 pts, 15 had grade 4 neutropenia at least once and 8 pts grade 4 thrombocytopenia. There was 18 episodes of infectious AEs and 11 of 18 were grade 3-4. There were no grade 5 AEs observed attributable to study drug. Conclusion: SGI-110 led to frequent grade 3-4 BM suppression in high risk AML/MDS pts when given as maintenance therapy after allo-SCT. However, bone marrow suppression was not associated with increased risk of infection and it was temporary with count recovery. The efficacy of SGI-110 has been promising with 1-year RFS of 66.3%. The study currently is ongoing. Disclosures Oran: Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Champlin:Actinium: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy. OffLabel Disclosure: The abstract presents interim analyses of a clinical trial investigating efficacy and safety of SGI-110 used as maintenance therapy in high risk AML and MDS patients after transplant.

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